Cellular Ca2+ Dynamics in Urinary Bladder Smooth Muscle From Transgenic Mice Overexpressing Na+-Ca2+ Exchanger

Murata, H.; Hotta, Shingo; Sawada, Eiji; Yamamura, Hisao; Ohya, Susumu; Kita, Satomi; Iwamoto, Takahiro; Imaizumi, Yuji

doi:10.1254/jphs.09319sc

Cited by 5 publications

(5 citation statements)

References 15 publications

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“…The enhanced Ca 2ϩ release detected in NCX1.3 tg/tg UBSM myocytes is presumably mediated by overfilling of the SR owing to enhanced Ca 2ϩ influx through NCX reverse mode, as CICR triggered by NCX reverse mode activity was previously reported in Na ϩ -loaded coronary arterial smooth muscle cells (12). Transgenic mice with doxycycline withdrawal-induced cardiac NCX1 overexpression exhibit increased SR Ca 2ϩ content and larger Ca 2ϩ transients (46), but SR Ca 2ϩ content measured by caffeine-induced Ca 2ϩ transients was not changed in NCX1.3 tg/tg UBSM myocytes (32). However, the possibility that Ca 2ϩ content in superficial, subplasmalemmal SR, which is preferentially filled by Ca 2ϩ influx via reverse mode NCX (7,44), is larger in NCX1.3 tg/tg cells is indicated by the increased amplitude and duration of the Ca 2ϩ transients/sparks.…”

Section: Discussionmentioning

confidence: 67%

“…Based on these results, it was suggested that NCX principally operates in the forward mode to extrude Ca 2ϩ in smooth muscle cells under normal physiological conditions. Accordingly, our previous study demonstrated that NCX1.3 tg/tg UBSM expressed a fourfold greater level of NCX1 protein compared with WT UBSM and that NCX1.3 overexpression potentiated the ability of forward mode Ca 2ϩ efflux to reduce the amplitude of the plateau phase of contractions induced by acetylcholine, high K ϩ , or direct electrical stimulation (32).…”

Section: Discussionmentioning

confidence: 90%

“…For example, we previously reported that Ca 2ϩ extrusion was enhanced after stimulation in urinary bladder smooth muscle (UBSM) of transgenic mice specifically overexpressing NCX1.3 in smooth muscles (NCX1.3 tg/tg ), whereas increased reverse mode activity was evident when the transmembrane Na ϩ gradient was reduced by reduction of extracellular [Na ϩ ] ([Na ϩ ] o ; Ref. 32). Significantly, reverse mode NCX activity was shown to predominate under resting conditions in vascular smooth muscle of NCX1.3 tg/tg mice leading to elevated systemic blood pressure and salt-sensitive hypertension, whereas a selective NCX inhibitor, SEA0400, was found to lower blood pressure in salt-dependent hypertensive animal models (23).…”

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confidence: 99%

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Overactive bladder mediated by accelerated Ca²⁺ influx mode of Na⁺/Ca²⁺ exchanger in smooth muscle

Yamamura

Cole

Kita

et al. 2013

American Journal of Physiology-Cell Physiology

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The Na(+)/Ca(2+) exchanger (NCX) is thought to be a key molecule in the regulation of cytosolic Ca(2+) dynamics. The relative importance of the two Ca(2+) transport modes of NCX activity leading to Ca(2+) efflux (forward) and influx (reverse) in smooth muscle, however, remains unclear. Unexpectedly, spontaneous contractions of urinary bladder smooth muscle (UBSM) were enhanced in transgenic mice overexpressing NCX1.3 (NCX1.3(tg/tg)). The enhanced activity was attenuated by KB-R7943 or SN-6. Whole cell outward NCX current sensitive to KB-R7943 or Ni(2+) was readily detected in UBSM cells from NCX1.3(tg/tg) but not wild-type mice. Spontaneous Ca(2+) transients in myocytes of NCX1.3(tg/tg) were larger and frequently resulted in propagating events and global elevations in cytosolic Ca(2+) concentration. Significantly, NCX1.3(tg/tg) mice exhibited a pattern of more frequent urination of smaller volumes and this phenotype was reversed by oral administration of KB-R7943. On the other hand, KB-R7943 did not improve it in KB-R7943-insensitive (G833C-)NCX1.3(tg/tg) mice. We conclude that NCX1.3 overexpression is associated with abnormal urination owing to enhanced Ca(2+) influx via reverse mode NCX leading to prolonged, propagating spontaneous Ca(2+) release events and a potentiation of spontaneous UBSM contraction. These findings suggest the possibility that NCX is a candidate molecular target for overactive bladder therapy.

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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 90%

mentioning

confidence: 99%

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Overactive bladder mediated by accelerated Ca²⁺ influx mode of Na⁺/Ca²⁺ exchanger in smooth muscle

Yamamura

Cole

Kita

et al. 2013

American Journal of Physiology-Cell Physiology

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“…NCX expression is highest in cardiac muscle, skeletal muscle, and brain tissue and has also been reported in vascular smooth muscle and urinary bladder smooth muscle (see Table ) (Murata et al ., ). NCX1 localizes at the presynaptic and postsynaptic sites and in the endoplasmic reticulum membrane of neurons (Canitano et al ., ), and high expression was also reported in axons, dendrites, and growth cones (Luther et al ., ).…”

Section: Distribution Of Sodium Calcium Antiportersmentioning

confidence: 97%

Recent structural and functional insights into the family of sodium calcium exchangers

Sharma

O'Halloran

2013

Genesis

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Maintenance of calcium homeostasis is necessary for the development and survival of all animals. Calcium ions modulate excitability and bind effectors capable of initiating many processes such as muscular contraction and neurotransmission. However, excessive amounts of calcium in the cytosol or within intracellular calcium stores can trigger apoptotic pathways in cells that have been implicated in cardiac and neuronal pathologies. Accordingly, it is critical for cells to rapidly and effectively regulate calcium levels. The Na(+) /Ca(2+) exchangers (NCX), Na(+) /Ca(2+) /K(+) exchangers (NCKX), and Ca(2+) /Cation exchangers (CCX) are the three classes of sodium calcium antiporters found in animals. These exchanger proteins utilize an electrochemical gradient to extrude calcium. Although they have been studied for decades, much is still unknown about these proteins. In this review, we examine current knowledge about the structure, function, and physiology and also discuss their implication in various developmental disorders. Finally, we highlight recent data characterizing the family of sodium calcium exchangers in the model system, Caenorhabditis elegans, and propose that C. elegans may be an ideal model to complement other systems and help fill gaps in our knowledge of sodium calcium exchange biology.

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“…Membrane fractions of the mouse pancreas and RINm5f cells were prepared as previously reported (25). The protein samples were subjected to SDS-PAGE on a 10% polyacrylamide gel.…”

Section: Western Blottingmentioning

confidence: 99%

Novel Spliced Variants of Large-Conductance Ca2+-Activated K+-Channel β2-Subunit in Human and Rodent Pancreas

et al. 2010

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Abstract. Large-conductance Ca 2+ -activated K + (BK) channel regulates action potential firing in pancreatic β-cells. We cloned novel spliced variants of the BK-channel β 2 -subunit (BKβ2b), which consisted of 36 amino acids including the N-terminal in the original human BKβ2 (BKβ2a), from human and rodent pancreas. Real-time PCR analysis showed the abundant expression of BKβ2b transcripts in human and rodent pancreas and also in the RINm5f insulinoma cell line. In addition, up-regulation of both BK-channel α-subunit (BKα) and BKβ2b transcripts was observed in pancreas tissues from diabetes mellitus patients. In HEK293 cells co-expressing BKα and BKβ2b, the inactivation of BK-channel currents, which is typical for BKα + BKβ2a, was not observed, and electrophysiological and pharmacological properties of BKα + BKβ2b were almost identical to those of BKα alone. In HEK293 cells stably expressing BKα, the transient co-expression of yellow fluorescence protein (YFP)-tagged BKβ2a proteins resulted in their distribution along the cell membrane. In contrast, the co-expression of YFP-tagged BKβ2b with BKα showed diffusely distributed fluorescence signals throughout the cell body. Taken together, the predominant splicing of BKβ2b versus that of BKβ2a presumably enhances the contribution of BK channels to membrane potential and may possibly be a factor modulating insulin secretion in a suppressive manner in pancreatic β-cells.

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Cellular Ca2+ Dynamics in Urinary Bladder Smooth Muscle From Transgenic Mice Overexpressing Na+-Ca2+ Exchanger

Cited by 5 publications

References 15 publications

Overactive bladder mediated by accelerated Ca²⁺ influx mode of Na⁺/Ca²⁺ exchanger in smooth muscle

Overactive bladder mediated by accelerated Ca²⁺ influx mode of Na⁺/Ca²⁺ exchanger in smooth muscle

Recent structural and functional insights into the family of sodium calcium exchangers

Novel Spliced Variants of Large-Conductance Ca2+-Activated K+-Channel β2-Subunit in Human and Rodent Pancreas

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Cellular Ca2+ Dynamics in Urinary Bladder Smooth Muscle From Transgenic Mice Overexpressing Na+-Ca2+ Exchanger

Cited by 5 publications

References 15 publications

Overactive bladder mediated by accelerated Ca2+ influx mode of Na+/Ca2+ exchanger in smooth muscle

Overactive bladder mediated by accelerated Ca2+ influx mode of Na+/Ca2+ exchanger in smooth muscle

Recent structural and functional insights into the family of sodium calcium exchangers

Novel Spliced Variants of Large-Conductance Ca2+-Activated K+-Channel β2-Subunit in Human and Rodent Pancreas

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Overactive bladder mediated by accelerated Ca²⁺ influx mode of Na⁺/Ca²⁺ exchanger in smooth muscle

Overactive bladder mediated by accelerated Ca²⁺ influx mode of Na⁺/Ca²⁺ exchanger in smooth muscle